ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.12553G>A (p.Ala4185Thr) (rs151119428)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000209969 SCV000265746 uncertain significance Malignant hyperthermia, susceptibility to, 1 2013-07-01 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV000376571 SCV000412869 likely benign Myopathy, Central Core 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000286723 SCV000412870 likely benign Multiminicore Disease 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000341753 SCV000412871 likely benign Neuromuscular disease, congenital, with uniform type 1 fiber 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000372650 SCV000412872 likely benign Malignant hyperthermia susceptibility 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000721276 SCV000590177 uncertain significance not provided 2018-02-06 criteria provided, single submitter clinical testing The A4185T variant was initially reported in an individual with malignant hyperthermia susceptibility per a positive in-vitro contracture test (IVCT); however, this individual harbored an additional RYR1 variant (Kravea et al., 2011). Subsequently, A4185T was reported as a variant of uncertain significance in an individual who had a likely malignant hypthermia episode in surgery, but a IVCT was not performed (MacKay et al., 2016). This variant is observed in 28/65996 (0.04%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
PreventionGenetics,PreventionGenetics RCV000721276 SCV000852300 uncertain significance not provided 2017-10-20 criteria provided, single submitter clinical testing
Invitae RCV000812854 SCV000953182 uncertain significance RYR1-Related Disorders 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 4185 of the RYR1 protein (p.Ala4185Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs151119428, ExAC 0.04%). This variant has been reported in individuals affected with malignant hyperthermia (PMID: 27555149, 21455645). ClinVar contains an entry for this variant (Variation ID: 224402). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This sequence change is located in a region of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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